Example 1 – Apoptosis And Aging
When we gain control of the gene responsible for the phenomenon of apoptosis, we will be in control of aging.
We are finding more evidence every day, indicating genetic links to all sorts of factors in the human being. We are just now beginning to scratch the surface of our own genetics. A landmark discover has just been unveiled:
In February , the two groups charting the human genome published their results—the entire 3 billion base pair sequence. The only definitive conclusion so far: Humans are far more complicated than we thought. …Eric Lander, director of the Whitehead Center for Genome Research in Cambridge, Massachusetts … adds: “within a decade, we will understand a lot about the causes of diseases. Understanding, however, does not translate into cures.” (Sinha 43)
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With this research, we will uncover more factors that our genetic code regulates, many factors that were previously believed to be random events. Spontaneous cell death, as it turns out is not spontaneous at all, but genetically predetermined at conception.
Cell death is an essential part of life. The cells in our bodies are constantly dividing, producing hundreds of thousands of new cells every second. To maintain balance, for every new cell, another cell must die. Our cells are programmed to kill themselves through a process called apoptosis. This in-built program of cell suicide prevents cancer by eliminating cells with damaged genes (Cotran 18). Similarly, our bodies replace cells with a new type of cell when a change is needed, such as during embryonic development (Cotran 18). To illustrate this point, we look at one of Dr. Adamchak’s “stories of physiology,” as taught from Martini, when a bone is being formed cartilage cells, or chondrocytes, come into an area to build a cartilage model of the bone. Once this model of bone is complete, the cartilage cells are given the command to die. Osteoblasts, or bone-building cells, move into space formerly occupied by the Condrocytes, and replace the cartilage matrix with a Calcium-rich, rock hard, matrix, we know as bone (188). In the foregoing example, there are instances of cells being told to die, this is programmed death, and known as apoptosis.
During life, our cells carry out metabolic functions, producing digestive enzymes and waste products, which are harmful to surrounding cells, if it spewed into the fluids among the cells. These enzymes and toxins must be packaged in a way that is not harmful to the interstitial environment, and in a manner in which appropriate cells in the region can readily absorb them. This must be done without invoking an inflammatory response (Browder).
Aging, also known as Senescence, is a natural process, “beginning at reproductive fitness and culminating in death,” Observed in most living organisms, senescence is characterized by a gradual reduction in “reserve capacity of organ systems”, (Heydari). Supporting research by U. of Florida’s Aging Biochemistry Laboratory indicates an increased apoptotic rate of cardiomyocytes, T-lymphocytes, and neurons, as age advances (Leeuwenburgh, par. 3.1). These factors manifest the classic signs of aging as well as many age-associated diseases, such as reduced cardiac function, susceptibility to illness and neurological disease (4.0).
Apoptotic cell death is only one factor of the aging mechanism. Normally, during development, as cells are “deleted” new cells are made to occupy the void. As an organism ages the number of dividing cells declines, resulting in a decreased capacity to heal. Every high school student knows that as cells divide, DNA is unzipped and re-zipped during the copying process. This process, by which we grow and heal, is believed to be responsible for our senescence.
Without some form of error correction, manipulation of DNA will result in damage to the codes contained in it. Error correction is provided by “The stuff at the end” of each chromosome string, as it literally translates from Latin, is known as a telomere (Cech). The telomere, a short string of amino acids, contains the error-correcting information required to properly duplicate DNA, however with each unzips the telomere becomes shorter until it is gone. The absence of the telomere results in damaged DNA, thus triggering apoptosis (Agin, Cech). DNA can also be damaged by exposure to forms of radiation including ultra-violet radiation from the sun.
As stated any damage to the genetic material results in the triggering of apoptosis (Schneider 67). The length of the telomere string is what limits the number of times the particular cell can divide, and by passing this information on to its issue, similarly limits any descendants to similar division. This is the safety mechanism that prevents normal cells from growing out of control and becoming a malignancy. The failure of this safety mechanism is what is seen in cells of breast cancer tumors (Cech).
The telomere theory is only one of many that allege controls over the apoptotic processes but is the leading focus of research for cancer centers throughout the world. Other leading theories include, hormonal control, and protein signaling devices, referred to as “factors”, a term often associated with compounds of either unknown origin or affect (Leeuwenburgh 2.0, Cothran 76, Cech).
Some common threads do exist among opposing theorists, in particular; the very genes that may hold the keys to eternal life, are the genes that allow cancer to spread. If these genes are disabled cancer is the result. Apoptosis, as stated, is the natural regulatory mechanism by which cancerous cells would be eradicated.
In order for our technology to achieve control over this phenomenon, we must first learn to control our leading killer today, cancer (Cech). After careful scrutiny of the latest research, as detailed herein, this technology is beyond our present grasp. Some day soon, we may find the keys to unlock the mysteries to our own genetic code, but what then will we do with it? Who we really want to live forever?
Among various types of programmed cell death associated with cancer cell proliferation inhibition, apoptosis is the most typical cell death mechanism, characterized by the activation of common caspases [Fulda and Debatin, 2006; Nakajima and Kuranaga, 2017]. Therefore, inhibition of the proliferation of cancer cells through the activation of the apoptosis pathway is the most fundamental research area for the discovery of novel anti-cancer agents.
Apoptosis accompanied by a specific morphological transformation including the formation of an apoptotic body by chromatin condensation is largely divided into death receptor (DR)-initiated extrinsic and mitochondria-mediated intrinsic pathways [Hengartner, 2000; Kaufmann et al., 2012].
Recently, it has been reported that AMPK may play an important role in the induction of apoptosis of cancer cells, and that excessive production of reactive oxygen species (ROS) stimulates AMPK activation [Liangpunsakul et al., 2008; Kaminskyy and Zhivotovsky, 2014]. Although studies on the ROS production and the role of AMPK are not fully understood, these results suggest that the AMPK signaling pathway may be a potential therapeutic target for inducing apoptotic cell death associated with mitochondrial function impairment.
Plants that have been used worldwide for a long time in traditional medicine have been constantly reviewed as resources for the development of new drugs to control various diseases. In particular, herbal medicines contain a large amount of biologically active substances with little side effects and can be used as an alternative treatment strategy for the prevention and treatment of various diseases including cancer [Wang et al., 2014; Ming-Hua et al., 2016].
Among them, citrus and dried peels have been used as traditional medicines to treat common colds, indigestion, and bronchial discomfort and have been reported to possess pharmacological effects on inflammation, allergies, diabetes, and viral infections [Min et al., 2014; Park et al., 2013; Oh et al., 2012; Suzuki et al., 2005]. A study using a tumor-bearing mouse model showed that Citrus unshiu Markovich peel extracts inhibited tumor growth associated with…
Apoptosis is a form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area. Apoptosis is ATP-dependent and is characterized by cell and organelle shrinkage, and membranes bleeding. Apoptosis plays a crucial role in developing and maintaining the health of the body by eliminating old cells, unnecessary cells, and unhealthy cells.
The human body replaces perhaps one million cells per second. When apoptosis does not work correctly, cells that should be eliminated may persist and become immortal, for example, in cancer and leukemia. When apoptosis works overly well as, it kills too many cells and inflicts grave tissue damage. This is the case in strokes and neurodegenerative disorders such as Alzheimer’s, Huntington’s, and Parkinson’s disease.
Apoptosis is also known as a programmed cell. Necrosis is ATP-independent and has its unique morphological characteristics such as increased cell or organelle volume (oncosis), Mitochondrial swelling, rupture of the plasma membrane (cellular leakage and consequent inflammation. Necrosis is the name given to the unprogrammed death of cells and living tissue. It is less orderly the apoptosis, which is part of programmed cell death.
In contact with apoptosis, which is part of programmed cell death. In contrast with apoptosis, the cleanup of cell debris by phagocytes of the immune system is generally more difficult as the disorderly death generally does not send cell signals which tell nearby phagocyte to engulf the dying cell.
This lack of signaling makes it harder for the immune system to locate and recycle dead cells that have died through necrosis than if the cell had undergone apoptosis. The release of intracellular content after membrane damage is the cause of inflammation in necrosis. There are many causes of necrosis including injury, infection, cancer, infarction, toxins, and inflammation. Severe damage to one essential system in the cell leads to secondary damage to other systems, s so-called “cascade of effects”.
Necrosis can arise from a lack of proper care to a wound site. Necrosis is accompanied by the release of special enzymes that are stored by lysosomes, which are capable of digesting cell components or the entire cell itself. The injuries received by cells may compromise the lysosome membrane or may initiate an unorganized chain reaction which causes the release of enzymes. Unlike Apoptosis, cells that die by necrosis may release harmful chemicals that damage other cells.
Tissue detection of necrosis is usually defined in a negative fashion by excluding other types of cell death, such as apoptosis and autophagic cell death. Although semi-quantification of tissue necrosis is possible based on histology, its gross quantification remains the same.
I have seen the effects of necrosis and what it does to the tissue cells. The damaged cell often dies, leaving horrible open decubitus ulcers that become difficult to heal. My brother was diagnosed with ESD (End-Stage Renal Disease). He was hospitalized for months.
During his stay at the hospital, there was a breakdown with tissue cells which eventually caused an ulcer. This type of circumstance could have definitely been avoided, however, it was not caught in time.
Apoptosis is a common programmed cell death that eliminates cells that are not required, dislocated or badly damaged in our body (Amaral, 2008). This process can trigger by two major pathways which are either intrinsic pathway or extrinsic pathway (Phillipyau, 2004).
Cellular stress or mitochondrial stress caused by DNA damage, radiation, nutrient deficiency, viral infection, and heat stock triggers the intrinsic pathway (Kabel et al, 2016). When a stress signal enters, the pro-apoptotic proteins in the cytoplasm (BAX and BID) bind to the outer membrane of the mitochondria and release a signal of the internal content (Fulda and Debatin, 2006).
The signal of BAX and BID is not enough to generate the reaction (Phillipyau, 2004). BAK is another proapoptotic protein that needed to promote the complete release of cytochrome C and the intramembrane content from the mitochondria (Fulda and Debatin, 2006). Cytochrome C forms a complex in the cytoplasm with adenosine triphosphate (ATP) and Apaf-1 enzyme. This complex activates an initiator protein called caspase-9 (Amaral, 2008).
The intrinsic pathway of apoptosis (Amaral, 2008). Activated caspase-9 reacts with the cytochrome C complex, ATP, and Apaf-1 to form an apoptosome. It will activate the effector protein known as caspase-3 that initiates degradation (Phillipyau, 2004). The release of cytochrome C from the intramembrane space, the intramembrane content released also contains apoptosis-inducing factor (AIF) to facilitate DNA fragmentation, and Smac/Diablo proteins to inhibit the inhibitor of apoptosis (IAP) (Fulda and Debatin, 2006).
In the extrinsic pathway, ligands (signal molecules) bind to transmembrane death receptors on the target cell to stimulate apoptosis (Kabel et al, 2016). Cells possess the Fas ligand (FasL) on their surface (Fulda and Debatin, 2006). FasL binds with the Fas receptors (a death receptor) on the target cell and triggers the aggregation of multiple receptors together on the surface of the target cell. To aggregate, these receptors recruit an adaptor protein known as Fas-associated death domain protein (FADD) on the cytoplasmic side of the receptors (Phillipyau, 2004). FADD recruits an initiator protein known as caspase-8 to form the death-inducing signal complex (DISC).
The recruitment of caspase-8 to DISC, caspase-8 will be activated and it directly activates an effector protein known as caspase-3 to initiate degradation of the cell. Activated caspase-8 converts BID protein to tBID, which acts as a signal on the membrane of mitochondria to initiate the release of cytochrome C in the intrinsic pathway (Fulda and Debatin, 2006).
The extrinsic pathway of apoptosis (Amaral, 2008). P53 protein is a specific DNA-binding protein that induces either cell cycle arrest or apoptosis in damaged or transformed cells (Kabel et al, 2016). It plays a major role in the DNA damage-induced ultraviolet (UV) radiation, toxins, and hormones (Fulda and Debatin, 2006).
The p53 gene regulates apoptosis by some important regulation mechanisms. Mdm2 is the main regulator of the p53 gene. Initially, p53 activates the expression of Mdm2. The p53 gene degrades by binding with the Mdm2 in the ubiquitin system. In normal cells phosphorylation of p53 prevents the binding of the Mdm2 gene to avoid degradation. Damaged DNA activates protein kinase (ATM, DNA-PK) to phosphorylate p53. It increases the p53 level which in turn increases Mdm2 release and initiates apoptosis (Phillipyau, 2004).
Kerr, Wyllie, and Currie first used the definition of apoptosis in a paper in 1972 to explain a morphologically distinct as a type of cell death, although particular the different parts of the apoptosis concept had been described years formerly. Our knowledge of the mechanisms mixed up in means of apoptosis in mammalian cells transpired from the research of programmed cellular death that occurs throughout the growth of the nematode Caenorhabditis elegans (Horvitz, 1999). Inside organism 1090 somatic cells are produced in development regarding the adult worm, in which 131 of those cells undergo apoptosis or “programmed cell death.”
These 131 cells die at specific points through the development procedure, that will be invariant between worms, demonstrating there is not any inflammatory response because of the procedure for apoptosis nor using the elimination of apoptotic cells because (1) apoptotic cells do not release their cellular constituents to the surrounding interstitial tissue; (2) they truly are quickly phagocytosed by surrounding cells hence probably preventing secondary necrosis; and, (3) the engulfing cells never produce anti-inflammatory cytokines. Distinguishing Apoptosis from Necrosis
The choice to apoptotic cell death is necrosis, which will be regarded as being a toxic procedure in which the cellular is a passive target and follows a power independent mode of death. Oncosis is used to describe a process leading to necrosis with karyolysis and cellular inflammation whereas apoptosis results in cell death with cell shrinkage, pyknosis, and karyorrhexis.
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Although the mechanisms and morphologies of apoptosis and necrosis differ, there is certainly an overlap between those two procedures. Necrosis and apoptosis represent morphologic expressions of a shared biochemical network referred to as the “apoptosis-necrosis continuum”. For instance, two factors that may transform a continuing apoptotic process into a necrotic process include a decline in the availability of caspases and intracellular ATP Whether a cell dies by necrosis or apoptosis depends partly on the nature associated with cell death signal, the muscle type, the developmental phase for the tissue and physiologic milieu (Zeiss, 2003).
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